Scientific article
Open access

Development of supramolecular anticoagulants with on-demand reversibility

Publication date2024-04-30
First online date2024-04-30

Drugs are administered at a dosing schedule set by their therapeutic index, and termination of action is achieved by clearance and metabolism of the drug. In some cases, such as anticoagulant drugs or immunotherapeutics, it is important to be able to quickly reverse the drug’s action. Here, we report a general strategy to achieve on-demand reversibility by designing a supramolecular drug (a noncovalent assembly of two cooperatively interacting drug fragments held together by transient hybridization of peptide nucleic acid (PNA)) that can be reversed with a PNA antidote that outcompetes the hybridization between the fragments. We demonstrate the approach with thrombin-inhibiting anticoagulants, creating very potent and reversible bivalent direct thrombin inhibitors ( K i = 74 pM). The supramolecular inhibitor effectively inhibited thrombus formation in mice in a needle injury thrombosis model, and this activity could be reversed by administration of the PNA antidote. This design is applicable to therapeutic targets where two binding sites can be identified.

Research group
Citation (ISO format)
DOCKERILL, Millicent et al. Development of supramolecular anticoagulants with on-demand reversibility. In: Nature biotechnology, 2024. doi: 10.1038/s41587-024-02209-z
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Article (Published version)
ISSN of the journal1087-0156

Technical informations

Creation05/06/2024 9:17:09 AM
First validation05/06/2024 11:35:54 AM
Update time05/06/2024 11:35:54 AM
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